Project Description: The mucosal surfaces of the respiratory tract are in direct contact with the surrounding environment, and as such are a primary portal of entry for human pathogens such as influenza and parainfluenza viruses. The significant public health threat that these viruses pose has highlighted the need for the development of more efficacious vaccines designed to promote robust and long-lasting pulmonary immunity. However, our incomplete understanding of how cellular immunity contributes to protection from respiratory viruses has complicated the development of safe and effective vaccines to these pathogens. To address this problem, we have investigated how virus-specific memory CD8+ T cells contribute to protection from a secondary virus infection. Our published studies have demonstrated that the rapid accumulation of circulating memory CD8+ T cells at the site of infection, such as the lung airways, play an important role in limiting early viral replication during a secondary challenge. However, the mechanism(s) by which memory CD8+ T cells recruited to the lung airways limit early viral replication are not known. Therefore, in the current application we will investigate the mechanism(s) that memory CD8+ T cells in the lung airways employ to limit early viral replication during a respiratory infection. First, we will investigate the regulation of cytolytic protein expression in memory CD8+ T cells, and how this expression is influenced by inflammatory cytokines. Second, we will extend these studies to determine how these molecules impact the cytolytic potential of memory CD8+ T cells and how this relates to protective immunity. Together, these studies will identify the mechanism(s) that govern the protective immunity mediated by memory CD8+ T cell in the lung airways and will be important for the rational design of cell- mediated vaccines to respiratory pathogens.